The compound 2,6-diisopropylphenol is a well known anesthetic agent that is commonly known as propofol. The onset of anesthesia is largely controlled by a drug's diffusion rate through the blood-brain barrier. Propofol is lipophilic, and this property helps that compound to provide rapid anesthetic action. However, the lipophilicity of propofol also renders that compound, which is a liquid at room temperature, relatively insoluble in water. As a result, propofol is commonly administered directly into the bloodstream (either by infusion or by bolus injection) as an oil-in-water emulsion. Such formulations typically contain a lipid component to solubilize the drug. Lipids, however, are good substrates for bacterial growth and can also be incompatible with preservatives that are at least somewhat water soluble such as benzyl alcohol. Further, parenteral administration of large volumes of lipid emulsions and/or the administration of lipid emulsions over prolonged periods of time may result in hyperlipidemia.
Despite these shortcomings of such oil-in-water emulsions, propofol has been a successful anesthetic and is commercially available for human administration as Diprivan® Injectable Emulsion (AstraZeneca; Diprivan® is a trademark of Imperial Chemical Industries PLC). Propofol is also marketed for veterinary use as Rapinovet™ Anesthetic Injection (Schering-Plough Animal Heath Corp.; Rapinovet™ is a trademark of Schering-Plough Veterinary Corp.) and as PropoFlo™ Anesthetic Injection (Abbott Laboratories; PropoFlo™ is a trademark of Abbott Laboratories).
Diprivan® Injectable Emulsion is a white, oil-in-water emulsion containing, in addition to 10 milligrams propofol per milliliter of emulsion, 100 mg soybean oil per mL, 22.5 mg glycerol per mL, 12 mg egg lecithin per mL, 0.005% disodium edetate, and sodium hydroxide. Diprivan® Injectable Emulsion is indicated as a single-use parenteral product. Diprivan® contains disodium edetate to retard the growth of microorganisms in the event of accidental extrinsic contamination. However, Diprivan® can still support the growth of microorganisms. As acknowledged in the product insert, there have been reports in which failure to use antiseptic techniques when handling the emulsion was associated with microbial contamination and associated medical complications. It is therefore necessary to discard tubing and unused portions of Diprivan® after 12 hours because of the potential for microbial contamination and growth. Diprivan® must also be stored in a very narrow temperature range between 4 to 22° C. (Diprivan® Injectable Emulsion Product Insert, AstraZeneca (2001)).
PropoFlo™ Anesthetic Injection is an oil-in water emulsion containing, in addition to 10 milligrams propofol per milliliter of emulsion, 100 mg soybean oil per mL, 22.5 mg glycerol per mL, 12 mg egg lecithin per mL, and sodium hydroxide. Like Diprivan®, PropoFlo™ is capable of supporting the growth of microorganisms. Failure to follow aseptic procedures may result in microbial contamination and associated medical complications. Unused portions of PropoFlo™ must therefore be disposed of within 6 hours of vial entry (PropoFlo™ Anesthetic Injection Product Insert, Abbott Laboratories (1998)).
Rapinovet™ Anesthetic Injection is a white, oil-in-water emulsion containing, in addition to 10 milligrams propofol per milliliter of emulsion, 100 mg soybean oil/mL, 22.5 mg glycerol/mL, 12 mg egg lecithin/mL, 0.25 mg sodium metabisulfite/mL, and sodium hydroxide. Like Diprivan® and PropoFlo™, Rapinovet™ is capable of supporting the growth of microorganisms. (Rapinovet™ Anesthetic Injection Product Insert, Schering-Plough Animal Health (2000)).
GB-A-1,472,793 (see also, U.S. Pat. Nos. 4,056,635; 4,452,817; and 4,798,846) describes the use of propofol as an anesthetic and discloses certain injectable formulations of that compound. These formulations use a range of non-ionic surfactant concentrations with a water miscible, non-aqueous co-solvent such as an alcohol or glycol to solubilize an effective concentration of propofol. For example, one such formulations combines propofol with propylene glycol and a polyoxyethylen-polyoxypropylene block co-polymer known as Pluronic® F68 (Pluronic is a registered tradename used by BASF Corporation, Parsippany, N.J.) in water. Pluronic® F68 is also commonly known as Poloxamer 188 or ‘P188’. However, the use of propylene glycol and other water-miscible co-solvents in such formulations is associated with undesirable medical side effects such as concomitant pain on injection, superficial thrombophlebitis and intravasal haemolytic reactions.
International patent publication No. WO 01/64187 describes aqueous preparations of propofol that use poloxamer block co-polymer and are free of propylene and other non-aqueous co-solvents. However, the publication notes that the poloxamer P188 has a very limited ability to hold propofol (only 0.8% propofol in a 10% aqueous solution of P188). As a result, the formulations described in this publication must contain mixtures of P188 and another poloxamer compound such as P407. Yet only the poloxamer P188 has been approved by the U.S. Food and Drug Administration (FDA) for use in injectable formulations. Moreover, the use of poloxamers and other block copolymers at high levels can also be associated with undesirable side effects and is generally undesirable. See, for example, Blonder et al., Life Sci. (1999) 65:PL261-266; and Johnston et al., J. Cardiovasc. Pharmacol. (1999) 34:831-842.
International patent publication no. WO 00/78301 also describes aqueous formulations of propofol in P188 or P407. However, the formulations disclosed in this publication also contain an additional surfactant, such as Solutol® HS 15 (Solutol is a registered trademark used by BASF Corporation, Parsippany, N.J.) or egg lecithin, or they contain co-solvents such as ethanol and/or polyethylene glycol. As noted above, however, the use of egg lecithin can support the growth of microorganisms, whereas co-solvents such as ethanol and polyethylene glycol can also be associated with undesirable side effects. Moreover, Solutol® is also associated with undesirable side effects and has not been approved for injectable formulations by the FDA.
Still other publications describe aqueous formulations that contain microemulsions of propofol in an oil or lipid. See, for example, International Patent Publication No. WO 00/10531. See also, U.S. Pat. Nos. 6,140,374; 6,150,423; and publication no. US 2002/0120015 A1.
Hence, there is an ongoing need for formulations of propofol and, in particular, for injectable, aqueous formulations of propofol that are sterile and stable for indefinite periods under clinical conditions. At the same time, there is a need for aqueous formulations of propofol that minimize the use of surfactants, block copolymers, co-solvents and other excipients that may produce harmful or undesired side effects.
The citation and/or discussion of a reference in this section and throughout the specification is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the invention described herein.